Aryl esters of tertiary carbamic acid



Patented Sept. 14, 1948 UNITED STATES PATENT OFFICE ABYL as'rans orgg'rmnr cannamc John A. Aeschlimann, Montclalr, N. 3., assignor toBoiImann-h Roche Inc., Nutley, N. 1., a corporation of New Jersey NoDrawing. Application June 25, 1946, Serial No. 879.288

In the above formula R. represents a phenyl radical substituted by anitrogen-containing group which can be in the form of a tertiary amine,or its salts. It is to be understood that the phenyl radical R maycontain other substituents in addition to the basic group. such asalkyi, aryl, branched alkyl or alkoxy. or aryloxy groups. R. representsa lower alkyl, aralkyl or aryl group as, for example, methyl, ethyl,propyl, butyl, benzyl or phenyl. Y represents a halogen as. for example,chlorine or bromine: a lower alkyl radical. as for instance, methyl,ethyl, propyl: an alkoxy group as. for example, methoxy, ethoxy orpropyloxy. n represents a small whole number from 1 to 5. Where 1: ismore than 1, the substituents represented by Y can be the same ordiiierent as, for example, alkyl and halogen. alkyl and alkoxy, alkoxyand halogen, or all three types of groups may be present.

The compounds as represented by the Formula A have been found to possessvaluable therapeutic properties. Thus, the 3-(methyl-para-substitutedaryl carbamoxylphenyl-trimethylammonium salts inhibit cholinesterasemore strongly than the unsubstituted S-(phenylmethylcarbamoxylphenyl-trimethylammonium salts. These novel compoundsexhibit a more powerful pharmacological action than physostigmine andthe carbamic esters disclosed in my U. 8. Patents No. 1,905,990 and2,208,485. The curare-like action on frogs rectus exerted by othercompounds of the general formula, such as the 1,2.3-1wlenyl analog whichhas a definite curarizing action, is surprising because theunsubstituted 3-(phenyl methylcarbamoxy) phenyl-trlmethylammonium saltacts as an antagonist to curare according to Brlscoe (Lancet 232, 621,1937). Such compounds can be utilized in the treatment of spasticconditions.

The substituted-aryl carbamic esters of phenolic bases can be readilyprepared by reacting 2 the corresponding substituted-aryl carbamylhaiides with the iree basic phenol or the basic metal phenolate. Thereaction can be illustrated by the following equation:

O B B-O-l'l-M rl-metal Hal The radicals have the same significance as inFormula A.

The proportion of the reagents employed may vary within wide limitsdepending on whether the free phenol is utilized or the metal salt, oran agent to bind the hydrogen chloride formed during the reaction. Wherethe free phenol is employed, it is preferred to employ one moi of thecarbamyl chloride to about two mols of the phenolic base. Where an acidbinding agent is employed, or the metal phenolate, the ratio may beapproximately one moi of a carbamyl chloride to one mo] of the phenol.However, it is not necessary to adhere to these proportions since it isto be understood that the reagents may be employed in any suitablereacting proportions.

The substituted-aryl carbamyl chlorides employed as intermediates forthe preparation of the esters are readily prepared by reacting phosgeneand the corresponding substituted-aryl secondary amines. This reactionis preferably carried out in the presence of a compound capable ofcombining with the hydrogen chloride formed during the reaction. Asexamples 0! such compounds there may be mentioned sodium hydroxide,potassium hydroxide, pyridine and the like. The halogen-substituted arylalkyl carbamyl chlorides can be obtained by halogenatlng the parentchloride.

While the substltuted-aryl alkyl carbamlc esters of phenolic bases areobtained in the form of tertiary amines, it is preferable to convert thebase into a salt as, for example. the hydrochloride. methyl sulfate,toluene-sulfonate, methiodide or methyl bromide quaternary salts. Thiscan be readily performed by treating the base with hydrogen chloride,methyl iodide, dimethyl sulfate. methyl bromide or p-tolusulfonate andsimilar quaternizlng reagents.

The following examples will serve to lllustrati some 0! the preferredmethods for carrying ow to the invention.

will 1 S-(p-tolyl-methvl carbamoxylphenul-trimethylammonium bromide Asolution of 50 grams of N-methyl-p-toluidine and 32.6 grams of pyridinein 200 cc. of xylene was added dropwise to 220 cc. of a 20% solution 01'phosgene in iwlene kept at l C. After 111- tration and distillation oithe xylene in vacuo, a crystalline residue remained. Afterrecrystallization from petroleum ether (B. P. 60-70 C.). N-methyl-p-tolyl carbamyl chloride was obtained which had an M. P. 68-71C. To a solution of 13.7 grams of N-dimethylamino phenol in 113 cc. of0.9 mol of alcoholic potassium hydroxide 10.4 grams of theN-methyl-p-tolyl carbamyl chloride were added and the mixture refluxedfor one hour. The potassium chloride formed was removed by filtrationand the filtrate evaporated in vacuo. The residue was dissolved in etherand washed with dilute sodium hydroxide. After drying and removal oi theether by distillation, there was obtained by distillation at 165- 170 C.and 0.15 mm. pressure 3-(p-tolyl-methylcarbamoxy) phenyl-dimethylamine.After standing several days in an acetone solution 01' methyl bromide,on addition of anhydrous ether 3-(ptolyl methylcarbamoxylphenyltrimethylammonium bromide crystallized. This product was recrystallizedfrom a mixture of ethanol and ether. M. P. 153-154 C. decomposition.

Examx2 3- (m-tolul-methyloarbomoxu) phenyl-trimethylammonium bromide Theprocedure was the same as in Example 1 except that in place 01' theN-methyl-p-toluidine there was employed the N-methyl-m-toluidine. Onreacting this amine with phosgene there was obtained N-methyl-3-tolylcarbamyl chloride with an M. P. of 53 C. When the latter compound wasreacted with m-dimethylamino phenol, there was obtained3-(m-tolyl-methylcarbamoxylphenyl-dimethylamine, B. P. fill-196 C. at0.13 mm. pressure. When the last-mentioned compound was combined withmethyl bromide there was obtained3-(m-tolyl-methyl-carbamoxylphenyl-trimethylammonium bromide, M. P. 150'C. decomposition.

Emu: 3

3-(o-tolul-methylcarbamoxy) phenyl-trimethylammonium bromide The series01 reactions employed to obtain the above-mentioned compound was thesame as in Example 1 except that for the N-methyl-ptoluidine there wasemployed the N-methyl-otoluidine. There was obtained N-methyI-Z- tolylcarbamyl chloride, M. P. 63-65;3-(o-tolylmethylcarbamoiw)phenyl-dimethylamine, B. P. 160-166" C. at0.15 mm.: and the above salt, M. P. 154-5 C. decomposition.

By following the same series of reactions but starting of! withp-methoxy methylaniline there was obtained the 3-(p-methoxyphenylmethylcarbamoxy) phenyl-trimethylammoniurn bromide.

Exams: 4

3- (p-cnlorphenyl-methulcurbamory) phenyltrimethvlammonium bromideN-methyl-p-chlorphenylcarbamyl chloride (M. P. 59-63 C.) was prepared ina manner similar to N-methyl-p-tolyl carbamylchloride by reactingp-chlormethylaniline with phosgene. On esterification of theN-methyl-p-chlorpheuylcarbamyl chloride with m-dimethylaminophenoi,there was obtained 3 (pchlorphenyl-methylcarbamoxilphenyl-dimethylamine, B. P. 191-196 C. at0.5 mm. The quaternary salt was obtained by treating the amine withmethyl bromide and was crystallized from a mixture of ethanol and ether.Its M. P. was 151-153 C. decomposition.

In a similar manner there was obtained the 3- orthoandmetachlorphenyi-methylearbamoxyphenyl trimethylammonium. bromides, M. P.161- 163 C. decomposition and M. P. 149-150" C. decomposition,respectively. The procedure ior obtaining these compounds involved thesubstitution of o-chloromethyl-aniline and m-chloromethylaniline for thep-chloromethylaniline.

The following intermediates were formed: N-methyl-o-chlorophenyi-carbamyl chloride (M. P. 50-52 C.),N-methyl-m-chlorphenylcarbamyl chloride (M. P. 83-85 CJ,3-(o-chloropheny1- methylcarbamoxy) phenyl-dimethylamine (B. P. 206-211C. at 2 mm.), and 3-(m-chlorophenylmethylcarbamoxy)phenyl-dimethylamine,(B. P. 195-200 at 1mm.)

Exmu: 5

3-0! methyl-233'-dimethylphenyl carbamoxy) phenyl-trimethylammoniumbromide The procedure in obtaining this compound was similar to that ofExample 1. l-methylarnino- 2,3-xylene was converted with phosgene tol-N- methyl-2,3-xylidyl carbamyl chloride, M. P. 40- 41 C. Onesterification of this compound with m-dimethylamino phenol, there wasobtained 3- (N-methyl 2',3 dimethylphenyl carbamoxy)phenyl-dimethylamine which had a B. P. o! 200- 205 C. at 0.9 mm.pressure. This compound could be ci'ysiallizcd from ethanol and wasiound to have an M. P. or 106-107 C. By quaternizing with methyl bromideand recrystallizing from a mixture of acetone and ether, 3-(N-methyl-2'3 -dimethylphenyl carbamoxy) phenyltrimethylammonium bromidewas obtained with an M. P. of 165-166 C. decomposition.

In a similar manner, starting from l-methylamino-2,4-xylene there wasobtained 3-(N- methyl 2',4'-dimethylphenyl carbamoxy)phenyltrirnethyl-ammonium bromide, starting from 1-methylamino-3,4-xylene there was obtained 3- (N methyl 3',4dimethylphenylcarbamoxy) phenyl-trimethylammonium bromide. (M. P. 156-7decomposition). The intermediate N- methyl, N-3,4-dimethylphenylcarbamyl chloride had an M. P. oi 61-63" C. and the corresponding3-(N-methyl 3',4' dimethylphenylcarbamoxy)phenyl-dimethylamine a B. P.of 187-195 C. at 0.45 mm.

Exmts 6 3- (methul-2,4-dibromophenyl carbamoxy) phenol trimethylammoniumbromide A solution of grams of 2,4-dibromo-N- methylaniline and 24 gramsof pyridine in 400 cc. of xylene was added slowly to 300 cc. 01' a 20%solution of phosgene in xylene at 10 to 0 C. After filtration and vacuumdistillation of the solvent, methyl-2,4-dibromophenyl carbamylchloridewas obtained. It could be recrystallized from petroleum ether (B. P.60-70), M. P. 79-81" C. A solution of 13.7 grams ofm-dimethylaminophenol in 93.5 cc. of 1.07 N sodium ethoxide in alcoholand 32.8 grams oi methyl-2,4-dibromophenylcarbamyl chloride was refluxedfor 1 hour. Sodium chloride was removed by filtration and the solventremoved by distillation in vacuo. The residue was taken up in ether andwashed with a dilute solution of sodium hydroxide. After drying andremoval of ether, the residue was distilled to remove a small fractionboiling at 135-145. The residue was dissolved in a solution of methylbromide in acetone. After several days, ether was added to give acrystalline precipitate of 3- (methyl-2,4-dibromophenylcarbamoxylphenyltrimethylammonium bromide. It could be recrystallizedfrom a mixture of alcohol and ether. M. P. 154-5" C.

Emma: 7

2- (methyl-p-tolyl-carbamozy) -5-phenylbenzul trimethylommontum bromideTo a solution of 22.7 grams of 3-dimethylaminomethyl-4-hydroxydiphenylin 93.5 cc. of 1.07 N sodium ethoxide in alcohol, are added 18.4 gramsof p-tolylmethylcarbamyl chloride and refluxed for 1 hour. Sodiumchloride was filtered ed and the alcohol removed by distillation invacuo. An ether solution of the residue was washed with dilute sodiumhydroxide. After drying and distillation oi the ether, the residue wasdistilled in high vacuum to remove a small amount of material boiling upto 160 at 0.3 mm. The residue (B. P. above 260/0.3 mm.) was then allowedto stand in an acetone solution of methyl bromide to give2-(methyl-p-tolylcarbamoxy) -5- phenylbenzyl trimethyl ammonium bromide.M. P. 206-207.5 C.

Following the procedure of the above examples there can also be obtainedcompounds in which the Y substituents may be mixed as, for example,3-(N-methyl 2-ch1or0-3' methylphenyl) carbamoxy-phenyl trimethylammcniumbromide, by starting on with the 2-chloro-3-methyl N- methyianiline.Likewise, there may be obtained the 3-(N methyl 2' ch1oro,4'methylphenyl carbamoxy) phenyl-trimethylammonium bromide by starting onwith 2-chloro-4-methyl N- methylaniline. The trihalogen-substitiitedphenyl alkyl carbamyl chlorides are readily obtainable lrom thetrihalogenated alkylanilines or by halogenation of the known phenylalkyl carbamyl chlorides, while the dihalogen tolu dines also formconvenient starting materials. By the same procedure as hereindescribed. these can be converted into the corresponding carbamicesters.

While most of the examples illustrate the invention in terms ofdlmethylaminophenols as the esterifying agent, it will be obvious thatthe other basic phenols may be employed; for instance,

one may employ as the esterifying agent o-hydroxy benzyldiethylamine,m-diethylamino phenol, hydroxyquinoline and the like.

While the compounds of the invention have also been illustrated in theabove examples in the form of their methyl bromide quaternary salts, itis also to be understood that any other suitable quaternizing orsalt-forming agents may be employed such as the methiodide,p-toluenesulfonate, methyl sulfate and the like.

The method for preparing the esters has been illustrated in terms ofreacting the substitutedaryl carbamyl halides with the free basic phenolor the basic metal phenolates, but the esters can also be prepared byother methods such as dedescribed in my U. S. Patent No. 1,905,990. Forinstance, the phenol can be converted to its chlorocarbonic ester andthis reacted with the appropriate amine, for example,N-methyl-p-toluidine in the case of preparing the p-tolyl-methylcarbamic esters.

The compounds in formula A where R is substituted by an aryl. aryloxy,or is a polycarbo- Mir" B being a member of the group consisting of aphenyl radical with a dialkyl amino group. a phenyl radical with adialkyl amino alkyl group. and a benzoheterocyelic radical. B being amember of the group consisting of a lower alkyl, aralkyl and arylradical, Y being a member of the group consisting of a halogen, a loweralkyl and an alkoxy radical, n being a small whole number from 1 to 5,and Y being the same or diflerent when n is more than one, and thequaternary salts thereof.

2. A composition as claimed in claim 1 in which the substituted-aryl isa halogenated aryl.

3. A compound as in claim 1 in which the suhstituted-aryl is analkylated ml.

4. A compound as in claim 1 in which the substituted-aryl iseblorophenyl.

5. Acompoundasinclaimiinwhichthesubstituted-aryl is methylphenyl.

6. Acompoundasinclaimlinwhichthesu stituted aryl is xyienyl.

7. 3-(p toyl methylcarbamoxy) phenyl trimethylammonium bromide.

8. 3 (p chlorophenyl methylcarbamoxy) phenyl-trimethylammonium bromide.

9. 3 (N methyl 2'3 dimethylphenylcarbamoxylphenyl-trimethylammoniumbromide.

10. The method which comprises esterifying through the hydroxyl group aphenol containing a basic substituent selected from the group consistingof diaikyl amino radicals, dialkyl amino alkyl radicals and abenzoheterocyclic radical with a carbamyl halide of the followingformula:

RU Halogen-C ON/ R' being a member of the group consisting of a loweralhrl, aralkyl, and aryl radical, Y being a member of the groupconsisting 01' a halogen, a lower alkyl and an alkoxy radical, n being asmall whole number from i to 5, Y being the same or difl'erent when n ismore than one, to form the corresponding substituted aryl oarbamic esterof the said phenol.

11. The method which comprises reacting phosguelne and a secondary amineof the following arm a:

R' being a member of the gro p consisting of a lower alkyl, aralkyl, andaryl radical, Y being a a member of the group consisting of a halogen, alower aliwl and an alkoxy radical, n being a small whole number from 1to 5, Y being the same or difl'erent when n is more than one, andreacting the resulting carbamyl chloride with a phenol containing abasic substituent selected from the group consistency of dialkyl aminoradicals, dialkyl amino alkyl radicals and abensoheterocyclic radical soas to form the corr sponding sub- 7 8 stltuted-aryl earbamie ester ofthe late phenol, Number Name one the sai Ph n l eln: aterlfled throulhthe hy- 1,905,990 Aeschltmann I Apr. 25, 1983 drew] noun. 2,208,485Aesehllmann II July 10, 1940 JOHN A. AnsOHHl-MNN. 5 OTHER mam REFERENCESCITED Stone, "Chem. Abstracts," vol. 22 (1920), pg.

422. The following references are of record in the Emma et I. out AmChem. soc-I" vol. 63 me this patent (1941), pp. soc-en.

UNITED BTATEB PATENTS 1o Franchlmont et 91., "Reculle des travaux chlm.Number Hum des Pays-Baa," vol. 18, III. 838.

1,258,293 Callsen Feb. 12, 1918 Certificate of Correction mm No.2,440,440. September 14, 1948.

JOHN A. AESCHLIMANN It is hereby certified that errors appear in theprinted specification of the above numbered patent requiring correctionas follows:

Column 4, line 17, for chlorophenyP' read chlorfhenyl; column 6, line22, claim 2, for "composition read compound; line 32, claim 7, or p-toylread p-tolyl; and that the said Letters Patent should be read with thesecorrections therein that the same may conform to the record of the casein the Patent Ofice.

Signed and sealed this 7th day of December, A. D. 1948.

THOMAS F. MURPHY,

4M flomm'cdowef PM.

7 8 stltuted-aryl earbamie ester of the late phenol, Number Name one thesai Ph n l eln: aterlfled throulh the hy- 1,905,990 Aeschltmann I Apr.25, 1983 drew] noun. 2,208,485 Aesehllmann II July 10, 1940 JOHN A.OTHER mam 5 REFERENCES CITED Stone, "Chem. Abstracts," vol. 22 (1920),pg.

422. The following references are of record in the Emma et I. out AmChem. soc-I" vol. 63 me this patent (1941), pp. soc-en.

UNITED BTATEB PATENTS 1o Franchlmont et 91., "Reculle des travaux chlm.Number Hum des Pays-Baa," vol. 18, III. 838.

1,258,293 Callsen Feb. 12, 1918 Certificate of Correction mm No.2,440,440. September 14, 1948.

JOHN A. AESCHLIMANN It is hereby certified that errors appear in theprinted specification of the above numbered patent requiring correctionas follows:

Column 4, line 17, for chlorophenyP' read chlorfhenyl; column 6, line22, claim 2, for "composition read compound; line 32, claim 7, or p-toylread p-tolyl; and that the said Letters Patent should be read with thesecorrections therein that the same may conform to the record of the casein the Patent Ofice.

Signed and sealed this 7th day of December, A. D. 1948.

THOMAS F. MURPHY,

4M flomm'cdowef PM.

